CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. Methylphenidate is a racemic mixture comprised of the d- and l-isomers. The d-isomer is more pharmacologically active than the l-isomer.
PHARMACOKINETICS
Absorption
Methylphenidate is readily absorbed. Following oral administration of CONCERTA® to adults, plasma methylphenidate concentrations increase rapidly reaching an initial maximum at about 1 to 2 hours, then increase gradually over the next several hours. Peak plasma concentrations are achieved at about 6 to 8 hours after which a gradual decrease in plasma levels of methylphenidate begins. CONCERTA® qd minimizes the fluctuations between peak and trough concentrations associated with immediate-release methylphenidate tid (see Figure 1). The relative bioavailability of CONCERTA® qd and methylphenidate tid in adults is comparable.
Figure 1. Mean methylphenidate plasma concentrations in 36 adults, following a single dose of CONCERTA® 18 mg qd and immediate-release methylphenidate 5 mg tid administered every 4 hours.
The mean pharmacokinetic parameters in 36 adults following the administration of CONCERTA® 18 mg qd and methylphenidate 5 mg tid are summarized in Table 1.
TABLE 1 Mean ± SD Pharmacokinetic Parameters
| Parameters |
CONCERTA®
(18 mg qd) (n=36) |
Methylphenidate
(5 mg tid) (n=35) |
|
Cmax(ng/mL)
|
3.7 ± 1.0
|
4.2 ± 1.0
|
|
Tmax(h)
|
6.8 ± 1.8
|
6.5 ± 1.8
|
|
AUCinf(ng·h/mL)
|
41.8 ± 13.9
|
38.0 ± 11.0
|
|
t1/2(h)
|
3.5 ± 0.4
|
3.0 ± 0.5
|
|
No differences in the pharmacokinetics of CONCERTA® were noted following single and repeated qd dosing indicating no significant drug accumulation. The AUC and t1/2 following repeated qd dosing are similar to those following the first dose of CONCERTA® 18 mg.
Dose Proportionality
Following administration of CONCERTA® in single doses of 18, 36, and 54 mg/day to adults, Cmax and AUC(0-inf) of d-methylphenidate were proportional to dose, whereas l-methylphenidate Cmax and AUC(0-inf) increased disproportionately with respect to dose. Following administration of CONCERTA®, plasma concentrations of the l-isomer were approximately 1/40th the plasma concentrations of the d-isomer.
Distribution
Plasma methylphenidate concentrations in adults decline biexponentially following oral administration. The half-life of methylphenidate in adults following oral administration of CONCERTA® was approximately 3.5 h.
Metabolism and Excretion
In humans, methylphenidate is metabolized primarily by de-esterification to (alpha)-phenyl-piperidine acetic acid (PPA) which has little or no pharmacologic activity. In adults the metabolism of CONCERTA® qd as evaluated by metabolism to PPA is similar to that of methylphenidate tid. The metabolism of single and repeated qd doses of CONCERTA® is similar.
After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose.
Food Effects
In patients, there were no differences in either the pharmacokinetics or the pharmacodynamic performance of CONCERTA® when administered after a high fat breakfast. There is no evidence of dose dumping in the presence or absence of food.
Special Populations
Gender
In healthy adults, the mean dose-adjusted AUC(0-inf) values for CONCERTA® were 36.7 ng·h/mL in men and 37.1 ng·h/mL in women, with no differences noted between the two groups.
Race
In adults receiving CONCERTA®, dose-adjusted AUC(0-inf) was consistent across ethnic groups; however, the sample size may have been insufficient to detect ethnic variations in pharmacokinetics.
Age
The pharmacokinetics of CONCERTA® has not been studied in children less than 6 years of age.
Renal Insufficiency
There is no experience with the use of CONCERTA® in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of PPA. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of CONCERTA®.
Hepatic Insufficiency
There is no experience with the use of CONCERTA® in patients with hepatic insufficiency.
CLINICAL STUDIES
CONCERTA® was demonstrated to be effective in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in three double-blind, active- and placebo-controlled studies in 416 children 6 to 12 years old. The controlled studies compared CONCERTA® given qd (18, 36, or 54 mg), methylphenidate given tid over 12 hours (15, 30, or 45 mg total daily dose), and placebo in two single-center, 3-week crossover studies (Studies 1 and 2) and in a multicenter, 4-week, parallel-group comparison (Study 3). The primary comparison of interest in all three trials was CONCERTA® versus placebo.
The Diagnostic and Statistical Manual, 4th edition, of the American Psychiatric Association (DSM-IV) provides criteria for three subtypes of ADHD (Combined Type, Predominantly Inattentive Type, or Predominantly Hyperactive-Impulsive Type). These criteria were used for diagnosis in all three studies.
Symptoms of ADHD were evaluated by community school teachers using the Inattention/Overactivity with Aggression (IOWA) Conners scale. Statistically significant reduction in the Inattention/Overactivity subscale versus placebo was shown consistently across all three controlled studies for CONCERTA® qd. The scores for CONCERTA® and placebo for the three studies are presented in Figure 2.
Figure 2: Mean Community School Teacher IOWA Conners Inattention/Overactivity Scores with CONCERTA® qd (18, 36, or 54 mg) and placebo. Studies 1 and 2 involved a 3-way crossover of 1 week per treatment arm. Study 3 involved 4 weeks of parallel group treatments with a Last Observation Carried Forward analysis at week 4. Error bars represent the mean plus standard error of the mean.
In two controlled studies (Studies 1 and 2), symptoms of ADHD were evaluated by laboratory school teachers using the SKAMP * laboratory school rating scale. The combined results from these two studies demonstrated significant improvements in attention and behavior in patients treated with CONCERTA® versus placebo that were maintained through 12 hours after dosing. Figure 3 presents the laboratory school teacher SKAMP ratings for CONCERTA® and placebo.
*Swanson, Kotkin, Agler, M-Fynn and Pelham
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